The prevalence of Alzheimer's disease (AD) is expected to rise significantly, reaching 15 million individuals by 2060 in the US. AD-related brain and cognitive changes are evident several years before symptom onset, in what is known as the preclinical stage. In the absence of disease-modifying treatments, it is imperative that we identify and characterize lifestyle factors that could modify the course of the disease. Greater aerobic fitness, objectively measured by VO2max, is considered a critical component of overall health and a strong predictor of cognitive functioning. It may prevent or modify the progression of AD, as it has been associated with stronger functional brain functioning and less amyloid and tau burden. It has also been shown to reduce neuroinflammation, which further contributes to disease progression and cognitive decline. While there is considerable evidence supporting the benefits of greater fitness in healthy aging, less is known about how it impacts the progression of AD. Specifically, there is paucity of research investigating, 1) the relation of fitness to AD-related brain pathology and functional connectivity; 2) the mechanisms that underlie the relationship between fitness and memory functioning in AD; and 3) changes in AD-related brain pathology, brain functioning and cognition associated with fitness overtime. The candidate will capitalize on an ongoing NIA-funded observational longitudinal biomarker study with a Colombian kindred with autosomal-dominant AD (ADAD), the world's largest family with a single mutation (E280A) in the Presenilin-1 gene that leads to dementia. She will test the hypothesis that greater aerobic fitness is associated with better brain functioning, less accumulation of brain pathology (tau and amyloid), and less neuroinflammation in presymptomatic mutation carriers. Some consider that ADAD is the ideal model to study preclinical changes associated with AD since mutation carriers, who are otherwise healthy (e.g. no cardiovascular pathology), will invariably develop dementia. Thus, this provides the opportunity to investigate the direct link between AD and aerobic fitness. To test the hypotheses, each participant will undergo PET PiB (amyloid) and 18F T807 (tau), functional MRI at rest, cognitive testing, and lumbar puncture to examine neuroinflammation as measured by a composite index of neuroinflammatory markers, at baseline and every 24 months. The candidate will obtain training in, (1) assessing aerobic fitness and understanding its relation to brain health, (2) longitudinal analytic approaches, (3) multimodal imaging methods, and (4) assessing and understanding the role of neuroinflammation in preclinical AD. She has gathered an exceptional team of experts in aging and AD from the MGH, Harvard University and Northeastern University, who are fully committed to helping her accomplish her research training and career development goals, as well as to ensure her successful transition to an independent and productive career in aging research.